Despite highly active antiretroviral therapy, HIV-infected individuals experience significant neurologic complications that range from HIV-associated dementia (HAD) to minor/moderate neurocognitive and motor impairments. These neurologic complications are more severe among HIV+ individuals co-morbid with substance abuse. Methamphetamine (Meth) is an extremely potent psychostimulant that is a drug-of- choice for men-who-have-sex-with-men, which enhances risky behaviors among drug users and in so doing is directly linked to the spread of HIV. Long-term Meth abuse is thought to be neurotoxic and its detrimental effects synergize with those associated with HIV neuropathogenesis. The mechanism(s) underlying this synergy remains unclear. Through the AIDS-Science Track Award for Research Transition (A-START/R03), this application will generate in vitro proof of principle studies to identify venue by which HIV and Meth potentiate neuropathology and in so doing provide a means for treating this co-morbidity. We propose that (i) the HIV protein, Tat, and Meth synergize to down regulate a key survival pathway for astrocyte and neurons (the Wnt/2-catenin pathway), the consequence of which is disruption of brain homeostasis and neurotoxicity, and ii) agents that upregulate Wnt/2-catenin will be neuroprotective against Tat and Meth-mediated neurotoxic effects. The rational for this hypothesis is that considerable data point to the Wnt/2-catenin pathway as a pro-survival pathway in the central nervous system (CNS), its down-regulation is linked to neurodegeneration, and work from our lab has demonstrated that HIV Tat diminishes Wnt/2-catenin activity. In this R03 application, will define the impact of Tat and Meth on Wnt/2-catenin activity and determine the biologic consequence of this modulation in the CNS. The paradigm selected for this application involves studies using in vitro (astrocytes, neurons, and mixed fetal brain culture) model systems. In aim 1, we will determine the impact of Tat and Meth on the Wnt/2-catenin pathway. In aim 2, we will assess the neuroprotective properties of agents (lithium and estrogen) that activate Wnt/2-catenin signaling against Meth and Tat-mediated neurotoxicity. These studies will provide proof of principle data pointing to the interplay between HIV, Meth, and the Wnt/2-catenin, which will facilitate future studies to evaluate this relationship in vivo. Ultimately, a better understanding of the mechanism by which Tat and Meth exert their synergistic effects on neuropathogenesis will expedite the development of activators of 2-catenin signaling to protect against Tat and Meth insults on the brain. PUBLIC HEALTH RELEVANCE: Drug abuse is a major health risk for acquiring HIV, whether through contaminated needles or compromising sound judgment that enhances the spread of HIV. Co-morbidity of psychostimulants and HIV increases neurologic complications than either agent alone. Methamphetamine (Meth) in particular is an extremely potent psychostimulant associated with HIV acquisition and NeuroAIDS. The reason for this is not clear. Through the AIDS-Science Track Award for Research Transition (A-START/R03), this application will generate proof of principle studies to identify venue by which HIV and Meth potentiate neuropathology. Our central idea is that the HIV protein Tat and Meth synergize to diminish Wnt/2-catenin signaling, which will then lead to the well-described neurotoxic effects of Meth and Tat co-morbidity. Further, we suspect that agents that activate the Wnt/2-catenin pathway will be neuroprotective against Tat and Meth neurotoxic effects. The rationale for this idea is that considerable data point to the Wnt/2-catenin pathway as a pro-survival pathway in the brain and we demonstrated that HIV Tat diminishes Wnt/2-catenin activity. In this small grant, we will test the idea that Tat and Meth synergize to diminish Wnt/2-catenin, evaluate the biologic consequence for this effect, and assess the neuroprotective properties of agents (lithium and estrogen) that activate Wnt/2- catenin signaling against Meth and Tat-mediated neurotoxicity. These studies will provide proof of principle for future studies to probe the interplay between HIV, Meth, and the Wnt/2-catenin pathway in an in vivo model system.